The chiral 1,2-substituted cyclopropyl carboxylic acid and chiral 1,2-substituted cyclopropyl amide derivatives are intermediate compounds useful for the preparation of chiral cyclopropyl amine derivatives of a general formula:
wherein R1, R2, R3, R3a, R3b, R4, and R5 are as defined below. Compounds of formula (II) are described in WO 2007150010, published on Dec. 27, 2007, corresponding to U.S. patent application Ser. No. 11/766,987, filed on Jun. 22, 2007, and U.S. patent application Ser. No. 11/956,816, filed on Dec. 14, 2007, each of which are all hereby incorporated by reference. The present invention offers a more efficient process to obtain chiral compounds of formula (II) via the chiral resolution of an aryl-cyclopropanecarboxylic acid with chiral amines. The chiral resolution step forms a diasteriomeric chiral salt, which is crystallized to obtain an enantiomerically pure salt. The enantiomerically pure arylcyclopropyl carboxylic acid is obtained upon breaking up the salt. The resulting enantiomerically pure cyclopropyl carboxylic acids can be reacted with various amines to form amides, which can be reduced to form chiral amine derivatives. The intermediate chiral amines can be further coupled with a desired aromatic or heteroaromatic reagent to provide compounds of formula (II).
Compounds of formula (II) have been identified as histamine H3 receptor antagonists. Various histamine H3 receptor antagonists are currently in clinical development for treatment of disease. Diseases for which histamine H3 receptor antagonists are under clinical study include, for example, schizophrenia, cognitive deficits of schizophrenia, Alzheimer's disease, narcolepsy, cataplexy, sleep disorder, hyperalgesia, allergic rhinitis, obesity, attention-deficit hyperactivity disorder, and dementia. Other conditions for which it is believed that histamine H3 receptor ligands can demonstrate therapeutic effect are deficits in attention, diseases with deficits of memory or learning, cognitive deficits and dysfunction in psychiatric disorders, mild cognitive impairment, epilepsy, seizures, and asthma, motion sickness, dizziness, Meniere's disease, vestibular disorders, vertigo, diabetes, type II diabetes, Syndrome X, insulin resistance syndrome, metabolic syndrome, pain, including neuropathic pain, neuropathy, pathological sleepiness, jet lag, drug abuse, mood alteration, bipolar disorder, depression, obsessive compulsive disorder, Tourette's syndrome, Parkinson's disease, and medullary thyroid carcinoma, melanoma, and polycystic ovary syndrome.
It would be beneficial to provide a more practical, economical, and robust processes for preparing the compounds having histamine H3 receptor activity to more efficiently supply histamine H3 receptor antagonist compounds for clinical studies and for eventual commercial supply. It would be particularly beneficial if the process provided the desired chiral compound using environmentally safe reagents under milder reaction conditions.